Elsevier

Thrombosis Research

Volume 180, August 2019, Pages 98-104
Thrombosis Research

Full Length Article
Atherosclerosis, myocardial infarction and primary hemostasis: Impact of platelets, von Willebrand factor and soluble glycoprotein VI

https://doi.org/10.1016/j.thromres.2019.06.014Get rights and content

Highlights

  • MPV is no marker for acute coronary syndrome in patients with atherosclerosis.

  • sGPVI and vWF-ratio show differences between patients with non-MI CAD versus CAD + MI.

  • None of the biomarkers or combinations is sufficient for daily care risk calculation.

Abstract

Introduction

Little is known about peril constellations in primary hemostasis contributing to an acute myocardial infarction (MI) in patients with already manifest atherosclerosis. The study aimed to establish a predicting model based on six biomarkers of primary hemostasis: platelet count, mean platelet volume, hematocrit, soluble glycoprotein VI, fibrinogen and von Willebrand factor ratio.

Materials and methods

The biomarkers were measured in 1.491 patients with manifest atherosclerosis of the Leipzig (LIFE) heart study. Three groups were divided: patients with coronary artery disease (900 patients) and patients with atherosclerosis and either ST-elevated MI (404 patients) or Non-ST-elevated MI (187 patients). Correlations were analyzed by non-linear analysis with Self Organizing Maps. Classification and discriminant analysis was performed using Learning Vector Quantization.

Results and conclusions.

The combination of hemostatic biomarkers is regarded as valuable tool for identifying patients with atherosclerosis at risk for MI. Nevertheless, our study contradicts this belief. The biomarkers did not allow to establish a predicting model usable in daily patient care. Good specificity and sensitivity for the detection of MI was only reached in models including acute phase parameters (specificity 0,9036, sensitivity 0,7937 in men; 0,8977 and 0,8133 in women). In detail, hematocrit and soluble glycoprotein VI were significantly different between the groups. Significant dissimilarities were also found for fibrinogen (in men) and von Willebrand factor ratio. In contrast, the most promising parameters mean platelet volume and platelet count showed no difference, which is an important contribution to the controversy concerning them as new risk and therapy targets for MI.

Introduction

Myocardial infarction (MI) is mainly caused by atherosclerosis [1]. While risk factors for atherosclerosis are extensively investigated, it remains controversial which factors lead to acute obstruction in patients with relevant atherosclerosis. Platelet adhesion and aggregation are central processes [1]. Beside platelets, subendothelial structures, coagulation proteins and rheologic factors are involved [2].

High platelet count (PLT) facilitates aggregation and increases secretion of thrombotic metabolites. Some authors confirmed a relationship between higher PLT and increased risk of adverse cardiovascular events [[3], [4], [5], [6], [7], [8]], others did not [3,[9], [10], [11]]. The effect on thrombus composition was shown by Kovács et al. [12].

Platelets with higher mean platelet volume (MPV) may contain more granules and be more effective [[13], [14], [15], [16], [17]]. MPV has been described as risk factor for an ACS [14,[17], [18], [19]] and was correlated with the severity of coronary artery disease (CAD) or mortality in patients with ACS [5,9,16,[20], [21], [22]]. Others failed to confirm such associations [10,20,23].

In blood vessels, erythrocytes concentrate centrally, whereas platelets are pushed to the wall. If hematocrit decreases, platelets adhere less effectively. A correlation between anemia and mortality in patients with ACS was demonstrated [24], but pathophysiology is explained non-hemostaseological.

Fibrinogen (FIB-C) facilitates platelet adhesion and cross linking of thrombocytes [25,26]. Sponder et al. observed a predictive correlation between fibrinogen and severity of CAD, confirming other studies [27]. Further, an association of fibrinogen and MI in contrast to unstable angina pectoris was shown [28]. Xu et al. found a link between fibrinogen and adverse cardiac events in patients with CAD [29]. In contrast, the extensive analysis of Ndrepepa et al. failed to identify fibrinogen as a risk factor for all-cause mortality [30].

The adhesion between subendothelial collagen and GPIb/IX/V on platelet surface is mediated by von Willebrand factor (vWF) and activates thrombocytes [25,26,[31], [32], [33]]. Metaanalyses conclude that elevated vWF is associated with major cardiovascular risk factors [[34], [35], [36]]. Several studies dealt with the association between vWF and the risk of CAD, MI or death following CAD in healthy subjects. Results were heterogeneous [[34], [35], [36], [37]] and little is known about the influence of the functionality of vWF expressed as ristocetin cofactor activity (vWF:RCo). We used vWF-ratio defined as vWF-antigen/ristocetin cofactor activity to overcome influence of acute phase reaction.

Glycoprotein VI (GPVI) is a collagen receptor on platelet surface mediating adhesion and activation [38], shed soluble GPVI (sGPVI) is a biomarker for platelet activation [39,40]. Higher expression of GPVI may lead to an easier activation of thrombocytes [41]. Elevated GPVI in patients with chest pain came along with higher risk for ACS and worse outcome. Further, GPVI was raised in patients with ambiguous ECG who finally suffered from ACS [42] and in patients with ACS in contrast to stable CAD. Patients with CAD presented with generally elevated levels of sGPVI [42]. Upregulated pathways for GPVI mediated platelet activation were found in patients with STEMI compared to CAD patients [41].

Recent works investigated antibodies against the GPVI-collagen-system as a target for antithrombotic therapy [43,44]. Diminishing the GPVI-function reduced platelet degranulation and platelet-endothelium interaction [45,46]. In a mouse model, the GPVI-antibody Revacept results in reduced infarct size [46] and in combination with low-dose thrombolysis in stroke, the therapy was effective but did not increase bleeding risk [47]. Further, it is under investigation in patients with stable CAD and symptomatic carotis stenosis, which highlights the importance of GPVI mediated adhesion of platelets in atherosclerosis [44].

In summary, the role of primary hemostasis in the development MI is still not known in detail. We aimed to identify risky constellations of primary hemostasis for MI in patients with CAD.

Section snippets

Materials and methods

Blood samples derive from 1491 patients from the Leipzig (LIFE) Heart Study [48]. All patients were suffering from coronary atherosclerosis with a lumen reduction of ≥50%. Group 0 includes only patients without MI and consists of patients either undergoing coronarangiography for the first time due to clinical suspiscion of coronary artery disease or patients with already known coronary artery disease. In the following, these are called non-MI CAD patients. Group 1 patients presented in the

Results

Men and women were analyzed separately mainly because of the different reference range of hematocrit in men and women. Analyzing men and women together, a distinction between non-MI CAD and MI by means of hematocrit is not possible because the distribution of high hematocrit values for women overlap with the normal range for men.

Metric data was described by measures of central tendency. Differences in distribution were calculated. Table 1 presents data of target parameters:

Hematocrit and sGPVI

Discussion

The risk to develop MI if atherosclerosis is manifest is still not predictable. The culprit lesion is often located proximal to the maximal stenosis [1]. Other factors besides degree of stenosis must influence time and severity of occlusion. We show the results of a large, well defined group of patients with manifest atherosclerosis with and without MI presenting data for primary hemostasis.

Conclusion

Many parameters may contribute to a vascular occlusion based on present atherosclerosis, but none of the biomarkers measured here is yet identified to have sole responsibility. The combination in a diagnostic model is regarded to identify patients at high risk, but our LVQ-model did not reveal a clinical useful score. A prospective, longitudinal model in which patients with CAD are monitored and investigated until the endpoint MI would be favorable. However, especially our results concerning

Sources of funding

The work was funded by Saxon State Ministry for Higher Education, Research and the Arts and supported by LIFE – Leipzig Research Center for Civilization Diseases, University Leipzig (LIFE-206 D32). LIFE is funded by the European Union, by the European Regional Development Fund (ERDF) and by the Free State of Saxony within the framework of the excellence initiative.

Contributors

JMV and TD collected the data, performed the analysis and wrote the manuscript, TV performed the calculation for LVQ and SOM. AT, RB and JT helped draft the manuscript and participated in study design and coordination. All authors read and approved the final manuscript.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

No prior presentation.

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